Tight junctions are the apical cell-cell adhesion that regulate paracellular permeability and are critical for epithelial cell polarity. Molecular architecture of tight junction has been studied extensively, which has confirmed that claudin family of proteins is integral component of tight junction. Loss of cell-cell adhesion is central to the cellular transformation and acquisition of metastatic potential; however, the role of claudin family of proteins play in a series of pathophysiological events, including human carcinoma development, is only now beginning to be understood. Several claudin mouse knockout models have been generated and the diversity of phenotypes observed clearly demonstrates their important roles in the maintenance of tissue integrity in various organs and suggest that claudins also participate in cellular contexts other than tight junctions. The mechanisms of claudin regulation and their exact roles in normal physiology and disease are being elucidated, but much work remains to be done. In this review, we have discussed the conceptual framework concerning claudins and their potential implication in cancer. We predict that next several years will likely witness a boom in our understanding of the potential role of claudins in the regulation of tumorigenesis, which may, in turn, provide new approaches for the targeted therapy.